title: Nature and mediators of parietal epithelial cell activation in glomerulonephritides of human and rat.
abstract: Bowman's capsule parietal epithelial cell activation occurs in several human proliferative glomerulonephritides. The cellular composition of the resulting hyperplastic lesions is controversial, although a population of CD133(+)CD24(+) progenitor cells has been proposed to be a major constituent. Mediator(s) involved in proliferation and migration of progenitor cells into the Bowman's space have been poorly explored. In a series of 36 renal biopsies of patients with proliferative and nonproliferative glomerulopathies, dysregulated CD133(+)CD24(+) progenitor cells of the Bowman's capsule invade the glomerular tuft exclusively in proliferative disorders. Up-regulation of the CXCR4 chemokine receptor on progenitor cells was accompanied by high expression of its ligand, SDF-1, in podocytes. Parietal epithelial cell proliferation might be sustained by increased expression of the angiotensin II (Ang II) type-1 (AT1) receptor. Similar changes of CXCR4, SDF-1, and AT1 receptor expression were found in Munich Wistar Frömter rats with proliferative glomerulonephritis. Moreover, an angiotensin-converting enzyme inhibitor normalized CXCR4 and AT1 receptor expression on progenitors concomitant with regression of crescentic lesions in a patient with crescentic glomerulonephritis. These results suggest that glomerular hyperplastic lesions derive from the proliferation and migration of renal progenitors in response to injured podocytes. The Ang II/AT1 receptor pathway may participate, together with SDF-1/CXCR4 axis, to the dysregulated response of renal precursors. Thus, targeting the Ang II/AT1 receptor/CXCR4 pathways may be beneficial in severe forms of glomerular proliferative disorders.
authors.affiliation: Mario Negri Institute for Pharmacological Research (IRCCS), Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rizzo
authors.affiliation: Mario Negri Institute for Pharmacological Research (IRCCS), Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Norberto
authors.initials: N
authors.lastname: Perico
authors.affiliation: Mario Negri Institute for Pharmacological Research (IRCCS), Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gagliardini
authors.affiliation: Mario Negri Institute for Pharmacological Research (IRCCS), Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Rubina
authors.initials: R
authors.lastname: Novelli
authors.affiliation: Centre for Tumour Biology, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
authors.forename: Malcolm R
authors.initials: MR
authors.lastname: Alison
authors.affiliation: Mario Negri Institute for Pharmacological Research (IRCCS), Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. Electronic address: giuseppe.remuzzi@marionegri.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.affiliation: Mario Negri Institute for Pharmacological Research (IRCCS), Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000096:biosynthesis; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology; D005921:Glomerulonephritis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000096:biosynthesis; D019718:Receptors, CXCR4 / Q000096:biosynthesis; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology
chemical_list: C515255:CXCL12 protein, human; C575935:CXCL12 protein, rat; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D018836:Inflammation Mediators; D044140:Receptor, Angiotensin, Type 1; D019718:Receptors, CXCR4; C488034:ACE protein, human; D007703:Peptidyl-Dipeptidase A